Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative

ABSTRACT

A pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a thiazolidinedione derivative is herein disclosed and described.

This is a continuation-in-part application of U.S. patent applicationSer. No. 10/664,803 filed on Sep. 19, 2003 now U.S. Pat. No. 7,785,627,and provisional patent application Ser. Nos. 60/412,180 and 60/412,181filed on Sep. 20, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to a pharmaceutical dosage form comprisingan antihyperglycemic drug, in combination with a thiazolidinedionederivative. More specifically, the present invention relates to an oraldosage form comprising a biguanide e.g. metformin or buformin or apharmaceutically acceptable salt thereof e.g., metformin hydrochlorideor the metformin salts described in U.S. Pat. Nos. 3,957,853 and4,080,472 which are incorporated herein by reference in combination witha thiazolidinedione derivative as described in U.S. Pat. No. 4,687,777also incorporated herein by reference.

Many techniques have been used to provide controlled andextended-release pharmaceutical dosage forms in order to maintaintherapeutic serum levels of medicaments and to minimize the effects ofmissed doses of drugs caused by a lack of patient compliance.

For example, extended release tablets have been described which have anosmotically active drug core surrounded by a semi-permeable membrane.These tablets function by allowing the aqueous components of a fluidsuch as gastric or intestinal fluid to permeate the coating membrane anddissolve the active ingredient so the resultant drug solution can bereleased through a passageway in the coating membrane. Alternatively, ifthe active ingredient is insoluble in the permeating fluid, it can bepushed through the passageway by an expanding agent such as a hydrogel.Some representative examples of these osmotic tablet systems can befound in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device wherein theactive agent is released from a core surrounded by a semipermeablemembrane only after sufficient pressure has developed within themembrane to burst or rupture the membrane at a weak portion of themembrane.

The basic osmotic device described in the above cited patents have beenrefined over time in an effort to provide greater control of the releaseof the active ingredient. For example, U.S. Pat. Nos. 4,777,049 and4,851,229 describe osmotic dosage forms comprising a semipermeable wallsurrounding a core. The core contains an active ingredient and amodulating agent wherein the modulating agent causes the activeingredient to be released through a passageway in the semipermeablemembrane in a pulsed manner. Further refinements have includedmodifications to the semipermeable membrane surrounding the active coresuch as varying the proportions of the components that form themembrane, e.g. U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 orincreasing the number of coatings surrounding the active core, e.g. U.S.Pat. Nos. 5,650,170 and 4,892,739.

Certain controlled or sustained release formulations that employantihyperglycemic drugs such as metformin hydrochloride have beenlimited to the use of an expanding or gelling agent to control therelease of the drug from the dosage form. This limited research isexemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE™ XRproduct insert which is a controlled release metformin HCl productcommercially available from Bristol-Myers Squibb Co.

Thiazolidinedione derivatives have been described in U.S. Pat. No.4,687,777. The therapeutic value of these compounds in combinationtherapy has further been described in U.S. Pat. Nos. 5,859,037;5,952,356; 5,965,584; 6,150,384 and 6,172,090. However, none of thesepatents describe a dosage form having the advantages of the subjectinvention.

Pharmaceutical dosage forms containing combinations of antihyperglycemicdrugs and thiazolidinedione derivatives have been proposed in the art.For example, EPO 0 749 751 (which is incorporated herein by reference)teaches pharmaceutical compositions comprising an insulin sensitivityenhancer, which could be a thiazolidinedione compound, in combinationwith other antidiabetics. More specifically, EPO 0 749 751 teaches thatthe preferred insulin sensitivity enhancer is pioglitazone, which can becombined with other antidiabetics such as metformin, phenformin orbuformin, and further that these drugs can be associated (mixed and/orcoated) with conventional excipients to provide taste masking orsustained release behavior. Another example of a combination ofantihyperglycemic drugs and thiazolidinedione derivatives is U.S. Pat.No. 6,011,049, (which is incorporated herein by reference). This patentteaches a single pharmaceutical composition that contains pioglitazoneor trolitazone and metformin in slow release forms such as osmotic pumpsor skin patches. Other combinations of antihyperglycemic drugs andthiazolidinedione derivatives can be found in U.S. Pat. Nos. 6,524,621;6,475,521; 6,451,342 and 6,153,632 and PCT patent applications WO01/35940 and WO 01/35941, which are incorporated herein by reference.

Also known in the art is WO 99/47125 and U.S. Pat. No. 6,099,862 thatdisclose a metformin osmotic tablet coated with an immediate releasecoating containing an antihyperglycemic or an hypoglycemic drug.

Although the prior art teaches pharmaceutical dosage formulations thatcontain both an antihyperglycemic compound and thiazolidinedionederivatives, the present invention provides numerous benefits over theprior art teachings as will be described below.

It is an object of the present invention to provide a dosage formcomprising a first active drug, which is formulated to provide acontrolled or sustained release delivery. Preferably, the first activedrug is an antihyperglycemic compound. The present invention furtherprovides for a second active drug which preferably is athiazolidinedione derivative. The novel dosage form described hereinprovides for delivery of first and second active drugs such that thebioavailability of either drug is not decreased by the presence of food.

It is a further object of the present invention to provide a dosageform, as described above, comprising delivery of a first active drug asa controlled or sustained release formulation for an antihyperglycemiccompound, wherein said controlled or sustained release mechanism is notregulated by an expanding polymer, in combination with delivery of asecond active drug by immediate release comprising a thiazolidinedionederivative.

It is also a further object of the present invention to provide a dosageform as described above, comprising delivery of a first active drug as acontrolled or sustained release formulation for an antihyperglycemiccompound in combination with delivery of a second active drug byimmediate release comprising a thiazolidinedione derivative that canprovide continuous and non-pulsating therapeutic levels of saidantihyperglycemic drug to an animal or human in need of such treatmentover a eight hour to twenty-four hour period.

It is an additional object of the present invention to provide a dosageform comprising delivery of a first active drug as a controlled orsustained release formulation for an antihyperglycemic compound incombination with delivery of a second active drug by immediate releasecomprising a thiazolidinedione derivative that obtains peak plasmalevels of the antihyperglycemic compound approximately 8-12 hours afteradministration and peak plasma levels of thiazolidinedione derivativeapproximately 1-4 hours after dosing.

It is also an object of the present invention to provide a dosage formcomprising a first active drug as a controlled or sustained releasepharmaceutical core tablet having only a homogeneous osmotic corewherein the osmotic core component may be made using ordinary tabletcompression techniques.

It is an additional object of the present invention to provide a dosageform comprising delivery of a first active drug as a controlled orsustained release formulation for an antihyperglycemic compound incombination with delivery of a second active drug by immediate releasecomprising a thiazolidinedione derivative that obtains peak plasmalevels of the antihyperglycemic compound approximately 8-12 hours afteradministration and peak plasma levels of thiazolidinedione derivativeapproximately 1-4 hours after dosing.

It is a further object of the present invention to provide a dosage formcomprising an antihyperglycemic drug as a controlled or sustainedrelease component and a thiazolidinedione derivative as a immediaterelease component, wherein not less than 85% of the total amount of thethiazolidinedione derivative is released from the dosage form within 45minutes or less.

It is a further additional object of the present invention to provide ashelf stable dosage form comprising an antihyperglycemic drug as acontrolled or sustained release component and a thiazolidinedionederivative as a immediate release component, wherein the total amount ofthiazolidinedione related compounds or impurities are not more than 0.6%after two years of storage and no individual related compound orimpurity is more than 0.2%.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical dosage form comprisinga first active drug, preferably an antihyperglycemic drug, incombination with a second active drug, preferably a thiazolidinedionederivative. More specifically, the present invention relates to an oraldosage form comprising a first active drug comprising a biguanide suchas metformin or buformin or a pharmaceutically acceptable salt thereofe.g., metformin hydrochloride or the metformin salts, in combinationwith a second active drug comprising a thiazolidinedione derivative

The foregoing objectives are met by a dosage form comprising a first andsecond active drug, wherein the first active drug is formulated as acontrolled release core, preferably an osmotic tablet, with or without agelling or expanding polymer. The second active ingredient may be partof the controlled release core or it may preferably be combined with thecontrolled release core in a manner that provides for immediate releaseof the second active ingredient. For example, the second activeingredient can be incorporated into a membrane that is applied to thecore or the second active ingredient may be applied to a coated oruncoated controlled release core.

In one embodiment the second active drug, which may be thethiazolidinedione derivative, is provided as an immediate releaseformulation in the dosage form whereas the antihyperglycemic componentis provided as a controlled release formulation in the dosage form. Thisimmediate release portion of the formulation should provide peak plasmalevels (T_(max)) of 1-12 hours preferably, 14 hours of thethiazolidinedione derivative, while the controlled release portion ofthe formulation may provide peak plasma levels (T_(max)) of 8-12 hoursof the antihyperglycemic component.

Preferably, the dosage form according to the subject invention may beadministered once a day, preferably with or after a meal, and mostpreferably with or after the evening meal. The subject dosage form canprovide therapeutic levels of the drug throughout the day with peakplasma levels (T_(max)) of the antihyperglycemic drug being obtainedbetween 8-12 hours after administration.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention concerns a pharmaceutical formulation or dosageform comprising a first active drug comprising an antihyperglycemic drugin combination with a second active drug comprising a thiazolidinedionederivative. Preferably, the antihyperglycemic drug is a biguanide e.g.metformin or buformin or a pharmaceutically acceptable salt thereof. Theantihyperglycemic drug is delivered in a controlled release manner froma tablet core, preferably an osmotic tablet core with or without agelling or swelling polymer. The tablet core should include theantihyperglycemic drug and at least one pharmaceutically acceptableexcipient. In one embodiment of the present invention the tablet coreincludes the antihyperglycemic drug, a binding agent and an absorptionenhancer, and the tablet core is preferably coated with a polymericcoating to form a membrane around the tablet and drilled to create onepassageway on each side of the membrane. The second active drugcomprises a thiazolidinedione derivative, and is preferably applied tothe membrane of the tablet core and provides for either immediate orcontrolled release of said thiazolidinedione derivative.

The term, antihyperglycemic drugs as used in this specification, refersto drugs that are useful in controlling or managing noninsulin-dependentdiabetes mellitus (NIDDM). Antihyperglycemic drugs include thebiguanides such as metformin, phenformin or buformin or the like, andpharmaceutically acceptable salts, isomers or derivatives thereof.

The term thiazolidinedione derivative as used in this specificationrefers to drugs that are useful for controlling or managing NIDDM. Theseinclude, but are not limited to, troglitazone, rosiglitazone,pioglitazone, ciglitazone or the like, and pharmaceutically acceptablesalts, isomers or derivatives thereof.

The term binding agent refers to any conventionally knownpharmaceutically acceptable binder such as polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, ethylcellulose, polymethacrylate, polyvinylalcohol,waxes and the like. Mixtures of the aforementioned binding agents mayalso be used. The preferred binding agents are water soluble materialssuch as polyvinyl pyrrolidone having a weight average molecular weightof 25,000 to 3,000,000. The binding agent may comprise approximatelyabout 0 to about 40% of the total weight of the core and preferablyabout 3% to about 15% of the total weight of the core. In oneembodiment, the use of a binding agent in the core is optional.

In a preferred embodiment, the core may optionally comprise anabsorption enhancer. The absorption enhancer can be any type ofabsorption enhancer commonly known in the art such as a fatty acid, asurfactant (anionic, cationic, amphoteric), a chelating agent, a bilesalt or mixtures thereof. Examples of some preferred absorptionenhancers are lecithin, fatty acids such as capric acid, oleic acid andtheir monoglycerides, surfactants such as sodium lauryl sulfate, sodiumtaurocholate and polysorbate 80, chelating agents such as citric acid,phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethyleneglycol-bis(β-aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The coremay comprise approximately 0 to about 20% of the absorption enhancerbased on the total weight of the core and most preferably about 2% toabout 10% of the total weight of the core.

In one embodiment of the present invention, which does not employ agelling or swelling polymer, the core of the present invention ispreferably formed by granulating an antihyperglycemic drug with abinding agent and compressing the granules with the addition of alubricant and absorption enhancer into a tablet. The core may also beformed by dry granulating the core ingredients by passing them through aroller compactor and compressing the granules with the addition of alubricant into tablets. Direct compression may also be employed fortabletting. Other commonly known granulation procedures are known in theart. Additionally, other excipients such as lubricants, pigments or dyesmay also be employed in the formulation of the subject invention.

The term gelling or swelling polymer refers to polymers that gel, swellor expand in the presence of water or biological fluids. Representativeexamples of gelling or swelling polymers are high molecular weighthydroxpropyl methylcellulose (such as METHOCEL® K100M, which iscommercially available from Dow Chemical) and high molecular weightpolyethylene oxides (such as POLYOX WSR 301, WSR 303 or WSR COAGULANT).Other gelling or swelling polymers are described in U.S. Pat. No.4,522,625 (which is incorporated herein by reference).

The core formed as described herein, can be coated with a membrane orsustained release coating. Materials that are useful in forming themembrane or sustained release coating are ethylcellulose, celluloseesters, cellulose diesters, cellulose triesters, cellulose ethers,cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate and cellulose acetate butyrate.Other suitable polymers are described in U.S. Pat. Nos. 3,845,770;3,916,899; 4,008,719; 4,036,228 and 4,612,008 (which are incorporatedherein by reference). The most preferred membrane or sustained releasecoating material is cellulose acetate comprising an acetyl content of39.3 to 40.3%, and is commercially available from Eastman FineChemicals.

In an alternative embodiment, the membrane or sustained release coatingcan include one of the above-described polymers and a flux-enhancingagent. The flux enhancing agent can increase the volume of fluid imbibedinto the core to enable the dosage form to dispense substantially all ofthe antihyperglycemic drug through the passageway and/or the porousmembrane. The flux-enhancing agent can be a water-soluble material or anenteric material. Examples of the preferred materials that are useful asflux enhancers are sodium chloride, potassium chloride, sucrose,sorbitol, mannitol, polyethylene glycols (PEG), propylene glycol,hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropylmethycellulose phthalate, cellulose acetate phthalate, polyvinylalcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68,LUTROL F127, LUTROL F108 which are commercially available from BASF) andmixtures thereof. A preferred flux-enhancer is PEG 400.

The flux enhancer may also be a drug that is water soluble such asmetformin or its pharmaceutically acceptable salts, or the flux enhancermay be a drug that is soluble under intestinal conditions. If the fluxenhancer is a drug, the present dosage form has the added advantage ofproviding an immediate release of the drug, that has been selected asthe flux enhancer.

The flux enhancing agent comprises approximately 0 to about 40% of thetotal weight of the coating, most preferably about 2% to about 20% ofthe total weight of the coating. The flux enhancing agent dissolves orleaches from the membrane or sustained release coating to form channelsin the membrane or sustained release coating which enables fluid toenter the core and dissolve the active ingredient.

The membrane or sustained release coating may also be formed using acommonly known excipient such as a plasticizer. Some commonly knownplasticizers include adipate, azelate, enzoate, citrate, stearate,isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyltri-n-butyl citrate, citric acid esters, and those described in theEncyclopedia of Polymer Science and Technology, Vol. 10 (1969),published by John Wiley & Sons. The preferred plasticizers aretriacetin, acetylated monoglyceride, grape seed oil, olive oil, sesameoil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate and the like. Depending on theparticular plasticizer, amounts from about 0 to about 25%, andpreferably about 2% to about 15% of the plasticizer can be used basedupon the total weight of the membrane or sustained release coating.

Generally, the membrane or sustained release coating around the corewill comprise from about 1% to about 10% and preferably about 2% toabout 5% based upon the total weight of the core and coating.

In a preferred embodiment, the membrane or sustained release coatingsurrounding the core further comprises a passageway that will allow forcontrolled release of the drug from the core. As used herein the termpassageway includes an aperture, orifice, bore, hole, weakened area oran erodible element such as a gelatin plug that erodes to form anosmotic passageway for the release of the antihyperglycemic drug fromthe dosage form. Passageways used in accordance with the subjectinvention are well known and are described in U.S. Pat. Nos. 3,845,770;3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607.

Independent of the antihyperglycemic is a second active drug, preferablya thiazolidinedione derivative. This second active drug may beformulated to provide an immediate release of the thiazolidinedionederivative. In one embodiment of the present invention thethiazolidinedione derivative is applied in the form of a layer to acontrolled or sustained released core comprising the antihyperglycemicdrug as a layer using a binder and other conventional pharmaceuticalexcipients such as absorption enhancers, surfactants, plasticizers,antifoaming agents and combinations of the foregoing. An absorptionenhancer may be present in the thiazolidinedione derivative layer in anamount up to about 30% w/w in comparison to the weight of thethiazolidinedione derivative. A binding agent may be present in anamount up to 150% w/w of the thiazolidinedione derivative. A secondactive drug immediate release formulation may be incorporated into asingle dosage form by coating onto the membrane or sustained releasecoating of the dosage form by conventional methods. Alternatively, itmay be incorporated by any pharmaceutically acceptable method into asingle dosage form with the first active drug. The incorporation of thesecond active drug may be performed by, but would not be limited to, theprocesses selected from the group consisting of drug layering,lamination, dry compression, deposition and printing.

When the thiazolidinedione derivative is coated onto a membrane orsustained release coating of an osmotic tablet core, thethiazolidinedione coating should be applied from a coating solution orsuspension that employs an aqueous solvent, an organic solvent or amixture of an aqueous and an organic solvent. Typical organic solventsinclude acetone, isopropyl alcohol, methanol and ethanol. If a mixtureof aqueous and organic solvents is employed, the ratio of water toorganic solvent should range from 98:2 to 2:98, preferably 50:50 to2:98, most preferably 30:70 to 20:80 and ideally about 25:75 to 20:80.If a mixed solvent system is employed, the amount of binder required forcoating the thiazolidinedione derivative onto the membrane or sustainedrelease coating may be reduced. For example, successful coatings havebeen obtained from a mixed solvent system where the ratio of binder tothiazolidinedione derivative is 1:9 to 1:11. Although acceptablecoatings can be obtained when the thiazolidinedione coat is applieddirectly to the membrane or sustained release coating, a preferredapproach is to first coat the membrane or sustained release coating witha seal coat prior to the application of the thiazolidinedione coating.As used herein a seal coat is a coating that does not contain an activepharmaceutical ingredient and that rapidly disperses or dissolves inwater.

The thiazolidinedione coating solution or suspension may also contain asurfactant and a pore forming agent. A pore forming is preferably awater-soluble material such as sodium chloride, potassium chloride,sucrose, sorbitol, mannitol, polyethylene glycols (PEG), propyleneglycol, hydroxypropyl cellulose, hydroxypropyl methycellulose,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such asLUTROL F68, LUTROL F127, LUTROL F108 which are commercially availablefrom BASF) and mixtures thereof. In an alternative embodiment, thedosage form of the present invention may also comprise an effectiveimmediate release amount of the antihyperglycemic drug. The effectiveimmediate release amount of antihyperglycemic drug may be coated ontothe membrane or sustained release coating of the dosage form or it maybe incorporated into the membrane or sustained release coating.

In addition, various diluents, excipients, lubricants, dyes, pigments,dispersants, etc., which are disclosed in Remington's PharmaceuticalSciences (1995), may be used to optimize the above listed formulationsof the subject invention.

Biguanides, such as metformin are commonly administered in dosage formscontaining 500 mg, 750 mg, 850 mg, and 1000 mg. Thiazolidinedionederivatives, for example pioglitizone, are commonly administered indosage forms containing 15 mg, 30 mg and 45 mg. The present invention isintended to encompass the above listed therapeutic combinations, withoutproviding a specific example of each possible combination of compoundsand their respective dosage amounts.

A preferred embodiment the dosage form will have the followingcomposition:

FIRST ACTIVE DRUG Core: Amount (% of core) drug 50-98% (75-95%preferred) binder 0.1-40%  (3-15% preferred) absorption enhancer  0-20%(2-10% preferred) lubricant 0-5% (0.5-1% preferred) Coating: Amount (%of coating) polymer 50-99% (75-95% preferred) flux enhancer  0-40%(2-20% preferred) plasticizer  0-25% (2-15% preferred)

SECOND ACTIVE DRUG Amount (% of total dosage form) drug 0.1-20%   (1-10%preferred) binder 0.1-30%   (1-15% preferred) surfactant 0-20% (0.1-15%preferred) pore former 0-25% (0.1-15% preferred) polymer (optional)0-30% (0.1-20% preferred)

The dosage forms prepared according to the present invention exhibit thefollowing dissolution profile when tested in a USP Type 2 apparatus at75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer)and at 37° C.:

Release of First Active Drug

Time (hours) % release 2  0-25% (0-15% preferred) 4 10-45% (20-40%preferred) 8 30-90% (45-90% preferred) 12 NLT 50% (NLT 60% preferred) 16NLT 60% (NLT 70% preferred) 20 NLT 70% (NLT 80% preferred) NLT = NOTLESS THANRelease of Second Active Drug

Time (hours) % release 0.5 NLT 60% (NLT 75% preferred)

It has been discovered that the selection of the excipients for use inthe thiazolidinedione component of the dosage form can greatly affectthe release characteristics, potency and stability of thethiazolidinedione. Therefore, in an alternate embodiment of the presentinvention, the composition of the thiazolidinedione component of thepresent invention should be selected so that not less than 85%,preferably not less than 90% and most preferably not less than 95% ofthe thiazolidinedione is released from the dosage form within 45minutes, preferably within 40 minutes and most preferably within 30minutes when tested according to the United States Pharmacopeia (USP)26, with Apparatus 1 at 100 rpm, 37° C. and 900 ml of 0.3 M KCl—HClBuffer, pH 2.0.

Further the excipients for use in the thiazolidinedione component of thedosage form should be selected so that the total thiazolidinedionerelated compounds or impurities in the final dosage form are not morethan 0.6%, preferably not more than 0.5% and most preferably not morethan 0.25% and each individual thiazolidinedione related compound orimpurity in the final dosage form is not more than 0.25%, preferably notmore than 0.2% and most preferably not more than 0.1%. Thethiazolidinedione related compounds or impurities in the final dosageform are determined by High Performance Liquid Chromatography (HPLC)using a YMC-ODS-AQ, 5 μm, 120 Å, 4.6×250 mm or equivalent column, a 0.1M ammonium acetate buffer:acetonitrile:glacial acetic acid (25:25:1)mobile phase, about a 40 μL injection volume, 0.7 mL/min flow rate, 25°C. column temperature and 269 nm wavelength for the UV detector.

EXAMPLES

The following are provided by way of example only and are in no meansintended to be limiting.

Example 1

A controlled release tablet containing 850 mg of metformin HCl and 15 mgpioglitazone is prepared as follows:

First Active Drug I. Core (% composition of core) Metformin HCl 90.54% Povidone K-30¹, USP 4.38% Sodium Tribasic Phosphate 4.58% Magnesiumstearate  0.5% ¹approximate molecular weight = 50,000; dynamic viscosity(10% w/v solution at 20° C.) = 5.5-8.5 mPa · s.(a) Granulation

The metformin HCl is delumped by passing it through a 40 mesh screen andcollecting it in a clean, polyethylene-lined container. The povidone,K-30, and sodium tribasic phosphate are dissolved in purified water. Thedelumped metformin HCl is then added to a top-spray fluidized bedgranulator and granulated by spraying the binding solution of povidoneand sodium tribasic phosphate under the following conditions: inlet airtemperature of 50-70° C.; atomization air pressure of 1-3 bars and sprayrate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

As stated above, the orifice may be formed by any means commonlyemployed in the pharmaceutical industry.

(c) Seal Coating (Optional)

The core tablet can be seal coated with an Opadry material or othersuitable water-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi and spray rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2-4% is obtained.

II Membrane (% composition of membrane) Cellulose Acetate (398-10)² 85%Triacetin 5% PEG 400 10% ²acetyl content 39.3-40.3%(a) Membrane Coating Process

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The clear membrane coating solution is then sprayed onto theseal coated tablets using a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars and spray rate of 120-150 ml/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

III. Second Active Drug Layering (% composition of second component)Pioglitizone HCl 43.5% Tween 80 2.0% Hydroxypropyl methylcellulose 54.5%

Tween 80 and hydroxypropyl methylcellulose are dissolved in purifiedwater. Pioglitizone HCl is then dispersed into this solution. Theresulting suspension is then sprayed onto the above-membrane-coatedtablets.

Example 2

A controlled release tablet containing 850 mg of metformin HCl and 15 mgpioglitazone is prepared as follows:

First Active Drug I. Core (% composition of core) Metformin HCl 88.555% Povidone K-90³, USP 6.368% Sodium Lauryl Sulfate 4.577% MagnesiumStearate  0.5% ³approximate molecular weight = 1,000,000, dynamicviscosity (10% w/v solution) 300-700 mPa · s at 20° C.(a) Granulation

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90, is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C.; atomization air pressureof 1-3 bars and spray rate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

As stated above, the orifice may be formed by any means commonlyemployed in the pharmaceutical industry.

(c) Seal Coating (Optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi and spray rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained.

II Membrane (% composition of membrane) Cellulose Acetate (398-10)⁴ 85%Triacetin 5% PEG 400 10% ⁴acetyl content 39.3-40.3%(a) Membrane Coating Process

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred. The coating solution is thensprayed onto the seal coated tablets in a fluidized bed coater employingthe following conditions: product temperature of 16-22° C.; atomizationpressure of approximately 3 bars and spray rate of 120-150 ml/min. Thesealed core tablet is coated until a theoretical coating level ofapproximately 3% is obtained.

III. Second Active Drug Layering (% composition of second component)Pioglitizone HCl 43.5% Tween 80 2.0% Hydroxypropyl methylcellulose 54.5%Tween 80 and hydroxypropyl methylcellulose are dissolved in purifiedwater. Pioglitizone HCl is then dispersed into this solution. Theresulting suspension is then sprayed onto the above described tablets.

Example 3

A controlled release tablet containing 500 mg of metformin HCl and 15 mgpioglitazone is prepared as follows:

I. First Active Drug

A 500 mg metformin membrane coated tablet is prepared as described inExample 2 above except that compound cup toolings are used duringtableting. The 500 mg metformin membrane coated tablet has the followingcomposition:

CORE Metformin HCl   500 mg/tablet Povidone K-90, USP  35.96 mg/tabletSodium lauryl sulfate, NF  25.84 mg/tablet Magnesium stearate, NF  2.82mg/tablet SEAL COATING Opadry Clear (YS-1-7006)  23.53 mg/tabletMEMBRANE COATING Cellulose Aacetate, 398-10, NF  23.56 mg/tabletTriacetin, USP  1.39 mg/tablet Polyethylene Glycol 400, NF  2.77mg/tablet Total weight 615.87 mg/tabletII. Second Active Drug Layering

An immediate release amount of pioglitiazone HCL is applied to the 500mg metformin HCl membrane coated tablet prepared in step I. The finaltablet has the following composition:

Metformin HCl membrane coated 615.87 mg/tablet Pioglitazone CoatingPioglitazone HCl  16.53 mg/tablet Tween 80   2.0 mg/tablet PolyplasdoneXL  15.0 mg/tablet Opadry Clear (YS-1-7006)  8.47 mg/tablet ColorCoating Opadry White  10.0 mg/tablet Polishing Coat Candelilla WaxPowder   2.0 mg/tablet

The pioglitazone coating is directly applied to the 500 mg metformin HClmembrane coated tablets. The pioglitazone coating is prepared bydissolving 0.252 kg of Opadry Clear, 0.269 kg of Polyplasdone XL and0.036 kg of Tween 80 in 9.908 kg of purified water using a homogenizer.Once these ingredients are dissolved, 0.296 kg of pioglitazone HCl isdispersed into the solution and homogenized. The homogenized dispersionis then directly applied to the 500 mg metformin HCl membrane coatedtablets using a 24″ O'Hara Labcoat III pan coater with the followingconditions:

Spray Rate 15-27 mL/min Exhaust Temperature 42-47° C. Atomization AirPressure 25 psi Pan Speed 5-9 rpm Inlet Air Flow 300-400 CFM

Once the pioglitazone coating has been applied to the 500 mgmetformin-HCl membrane coated tablet, an aesthetic or color coating ofOpadry white is applied to the pioglitazone coated tablet. The colorcoating is prepared by dispersing 0.179 kg of Opadry White in 1.791 kgof purified water. The Opadry White suspension is applied to thepioglitazone coated tablet using a 24″ O'Hara Labcoat III pan coaterunder the following conditions:

Spray Rate 20-35 mL/min Exhaust Temperature 35-45° C. Atomization AirPressure 25 psi Pan Speed 9 rpm Inlet Air Flow 390-500 CFM

Once the color coating is applied, the tablets are polished using 0.036kg of Candelilla wax powder.

Example 4

A controlled release tablet containing 500 mg of metformin HCl and 15 mgpioglitazone is prepared as follows:

I. First Active Drug

A 500 mg membrane coated tablet is prepared as described in Example 2above except that compound cup toolings are used during tableting. The500 mg membrane coated tablet has the following composition:

CORE Metformin HCl   500 mg/tablet Povidone K-90, USP  35.96 mg/tabletSodium Lauryl Sulfate, NF  25.84 mg/tablet Magnesium Stearate, NF  2.82mg/tablet SEAL COATING Opadry Clear (YS-1-7006)  23.53 mg/tabletMEMBRANE COATING Cellulose Acetate, 398-10, NF  23.56 mg/tabletTriacetin, USP  1.39 mg/tablet Polyethylene Glycol 400, NF  2.77mg/tablet Total weight 615.87 mg/tabletII. Second Active Drug Layering

An immediate release amount of pioglitiazone HCL is applied to the 500mg metformin HCl seal coated tablet prepared in Step I. The final tablethas the following composition:

Metformin HCl membrane coated tablet 615.87 mg/tablet Seal Coat OpadryClear (YS-1-7006)  13.8 mg/tablet Pioglitazone Coating Pioglitazone HCl 16.53 mg/tablet Tween 80   2.0 mg/tablet Sodium Chloride  4.27mg/tablet Opadry Clear (YS-1-7006)   2.0 mg/tablet Color Coating OpadryWhite  8.10 mg/tablet Polishing Coat Candelilla Wax  0.20 mg/tablet

The seal coating solution is prepared by dissolving 0.258 kg of OpadryClear in 2.576 kg of purified water and spraying the solution ontoapproximately 12.088 kg of the 500 mg membrane coated metformin HCltablet cores using a 24″ O'Hara Labcoat III pan coater. The seal coat isapplied under the following conditions:

Spray Rate 20-35 mL/min Exhaust Temperature 35-45° C. Atomization AirPressure 25 psi Pan Speed 9 rpm Inlet Air Flow 390-500 CFM

The pioglitazone coating is applied to the seal coated 500 mg metforminHCl membrane coated tablets. The pioglitazone coating is prepared bydissolving 0.040 kg of Opadry Clear, 0.085 kg of sodium chloride and0.040 kg of Tween 80 in 4.915 kg of purified water using a homogenizer.Once these ingredients are dissolved, 0.328 kg of pioglitazone HCl isdispersed into the solution and homogenized. The homogenized dispersionis then applied to the seal coated 500 mg metformin HCl membrane coatedtablets using a 24″ O'Hara Labcoat III pan coater with the followingconditions:

Spray Rate 10-30 mL/gun/min Exhaust Temperature 35-45° C. AtomizationAir Pressure 20-40 psi Pattern Air Pressure 20-40 psi Pan Speed 8-12 rpmInlet Air Flow 250-450 CFM.

Once the pioglitazone coating has been applied to the seal coated 500 mgmetformin HCl membrane coated tablets, an aesthetic or color coating ofOpadry White is applied to the pioglitazone coated tablet. The colorcoating is prepared by dispersing 0.159 kg of Opadry. White in 1.585 kgof purified water. The Opadry White suspension is applied to thepioglitazone coated tablet using conditions similar to those describedabove for application of the seal coating. Once the color coating isapplied, the tablets are polished using 0.004 kg of Candelilla waxpowder.

Example 5

A controlled release tablet containing 1000 mg of metformin HCl and 30mg pioglitazone is prepared as follows:

I. First Active Drug

A 1000 mg metformin membrane coated tablet is prepared as described inExample 3 above. The 1000 mg membrane coated tablet has the followingcomposition:

CORE Metformin HCl   1000 mg/tablet Povidone K-90, USP  78.0 mg/tabletSodium Lauryl Sulfate, NF  51.69 mg/tablet Magnesium Stearate, NF  5.66mg/tablet SEAL COATING Opadry Clear (YS-1-7006)  47.05 mg/tabletMEMBRANRE COATING Cellulose Acetate, 398-10, NF  15.77 mg/tabletTriacetin, USP  0.92 mg/tablet Polyethylene Glycol 400, NF  1.85mg/tablet Total weight 1201.0 mg/tabletII. Second Active Drug

An immediate release amount of pioglitazone HCL is applied to the 1000mg metformin HCl membrane coated tablets prepared in step I. The finaltablet has the following composition:

Metformin HCl membrane coated tablet 1201.0 mg/tablet Seal CoatingOpadry Clear (YS-1-7006)  16.0 mg/tablet Pioglitazone CoatingPioglitazone HCl  33.06 mg/tablet Sodium Chloride  4.27 mg/tablet OpadryClear (YS-1-7006)   3.0 mg/tablet Color Coating Opadry II White(Y-22-7719)  20.27 mg/tablet Polishing Coat Candelilla Wax Powder  0.40mg/tablet

The seal coating is prepared by dispersing 0.174 kg of Opadry Clear in3.478 kg of ethanol and mixing the dispersion for 15 minutes. Thedispersion is then sprayed onto approximately 13.174 kg of the 1000 mgmetformin HCl membrane coated tablets using a 24″ O'Hara Labcoat III pancoater. The seal coat is applied to the 1000 mg metformin HCl membranecoated tablets with the following conditions:

Spray Rate 10-30 ml/gun/min Exhaust Temperature 25-45° C. AtomizationAir Pressure 20-40 psi Pan Speed 6-12 rpms Pattern Air Pressure 20-40psi Inlet Air Flow 250-450 CFM

The pioglitazone coating then is applied to the seal coated 1000 mgmetformin HCl membrane coated tablets. The pioglitazone coating isprepared by dissolving 0.036 kg of Opadry Clear and 0.046 kg of sodiumchloride in 5.344 kg of ethanol using a homogenizer. Once theingredients are dispersed, 0.359 kg of pioglitazone HCl is dispersedinto the solution and homogenized. The homogenized dispersion is thenapplied to the seal coated 1000 mg metformin HCl membrane coated tabletsusing a 24″ O'Hara Labcoat III pan coater with the following conditions:

Spray Rate 10-30 mL/gun/min Exhaust Temperature 25-45° C. AtomizationAir Pressure 20-40 psi Pan Speed 6-12 rpm Pattern Air Pressure 20-40 psiInlet Air Flow 250-450 CFM

Once the pioglitazone coating has been applied, an aesthetic or colorcoating of Opadry II White is applied to the pioglitazone coated tablet.The color coating is prepared by dispersing about 0.220 kg of Opadry IIWhite in 4.407 kg of ethanol. The Opadry II White suspension is thenapplied to the pioglitazone HCl coated tablets using a 24″ O'HaraLabcoat III pan coater using conditions similar to those described abovefor the seal coating. Once the color coating is applied, the tablets arepolished using 0.004 kg of Candelilla wax powder.

Example 6

A controlled release tablet containing 1000 mg of metformin HCl and 30mg pioglitazone is prepared as follows:

I. First Active Drug

A 1000 mg membrane coated tablet is prepared as described in Example 3above. The 1000 mg membrane coated tablet has the following composition:

CORE Metformin HCl  1000 mg/tablet  Povidone K-90, USP 78.0 mg/tabletSodium Lauryl Sulfate, NF 51.69 mg/tablet  Magnesium Stearate, NF 5.65mg/tablet SEAL COATING Opadry Clear (YS-1-7006) 47.05 mg/tablet MEMBRANE COATING Cellulose Acetate, 398-10, NF 15.77 mg/tablet Triacetin, USP 0.92 mg/tablet Polyethylene Glycol 400, NF 1.85 mg/tabletTotal weight 1201.0 mg/tablet II. Second Active Drug

An immediate release amount of pioglitazone HCL is applied to the 1000mg metformin HCl membrane coated tablets prepared in step I. The finaltablet has the following composition:

Metformin HCl membrane coated tablet 1201.0 mg/tablet  Seal Coat OpadryClear (YS-1-7006) 21.0 mg/tablet Pioglitazone Coating Pioglitazone HCl33.06 mg/tablet  Sodium Chloride  5.0 mg/tablet Opadry Clear (YS-1-7006) 3.7 mg/tablet Color Coating Opadry II White (Y-22-7719) 21.54mg/tablet  Polishing Coat Candelilla Wax Powder 0.40 mg/tablet

The seal coat is applied to the 1000 mg metformin HCl membrane coatedtablet. The seal coating is prepared by dispersing 0.229 kg of OpadryClear in 4.573 kg of alcohol USP and mixing the dispersion for 15minutes. The dispersion is then sprayed onto approximately 13.08 kg ofthe 1000 mg metformin HCl tablet cores using a 24″ O'Hara Labcoat IIIpan coater with the nozzle tip set 4±2″ from the top of the static bedand the following conditions:

Spray Rate 25 ± 10 mL/gun/min Exhaust Temperature 25° C. ± 5° C.Atomization Air Pressure 10-40 psi Pan Speed 4-9 rpm Supply Air Flow 200± 100 CFM Pattern Air Pressure 10-40 psi

The seal coating dispersion is continuously stirred until it is consumedduring the coating process.

The pioglitazone coating then is applied to the seal coated 1000 mgmetformin HCl membrane coated tablets. The pioglitazone coating isprepared by mixing 4.434 kg of alcohol USP and 1.250 kg of purifiedwater (approximately a 78:22 alcohol to purified water ratio) and slowlydispersing 0.040 kg of Opadry Clear into the solvent mixture. Once theOpadry Clear is dispersed, it is homogenized for about 10 minutes. Oncethe Opadry Clear dispersion is homogenized, 0.054 kg of sodium chlorideis added to the dispersion and homogenized for about 2 minutes. Afterthe sodium chloride is homogenized, 0.360 kg of pioglitazone HCl isslowly dispersed into the solvent mix and then homogenized for about 10minutes. Once the pioglitazone HCl is homogenized, the homogenizer isremoved from the mixing vessel and replaced with an air mixer and mixedfor an additional 15 minutes. The pioglitazone suspension is stirreduntil the suspension is consumed during the coating process. Thepioglitazone HCl suspension is applied to the seal coated 1000 mgmetformin HCl membrane coated tablet cores using a 24″ O'Hara LabcoatIII pan coater with the nozzle tip set 4±2″ above the top of the staticbed with the following conditions:

Spray Rate 25 ± 10 mL/gun/min Exhaust Temperature 25 ± 5° C. AtomizationAir Pressure 10-40 psi Pan Speed 4-9 rpms Pattern Air Pressure 10-40 psiSupply Air Flow 200 ± 100 CFM

Once the pioglitazone coating has been applied to the seal coated 1000mg metformin HCl membrane coated tablets, an aesthetic coating of OpadryII White is applied to the pioglitazone coated tablet. The aestheticcoating is prepared by dispersing 0.235 kg of Opadry II White(Y-22-7719) in 4.691 kg of alcohol USP and mixing the dispersion forabout 1 hour. The Opadry II White dispersion is then sprayed onto thepioglitazone HCl coated tablets using a 24″ O'Hara Labcoat III pancoater with the nozzle tip set at 4±2″ from the top of the static bedand the following conditions:

Spray Rate 25 ± mL/gun/min Exhaust Temperature 25° C. ± 5° C.Atomization Air Pressure 10-40 psi Pan Speed 4-9 rpm Supply Air Flow 200± 100 CFM Pattern Air Pressure 10-40 psi

The color coating dispersion is continuously stirred until thedispersion is consumed during the coating process.

Once the aesthetic coating suspension is consumed, the tablets are driedin the coating pan for about 5 minutes with a pan speed of about 2-8rpms and an exhaust temperature of 25±5° C. Once the tablets are dried,the exhaust air is turned off and the pan speed is adjusted to about 3-4rpms and 0.004 kg of Candellia wax powder that had been passed through a60 mesh screen is sprinkled onto the tablets. After the tablets haverolled in the wax for about 5 minutes the exhaust air is turned on andthe tablets are rolled for an additional 10 minutes.

The finished polished tablet exhibited the following pioglitazone HCldissolution profile when tested in a USP apparatus type 1 at 100 rpm ina pH 2.0 HCl-0.3M KCl buffer solution:

Time % Pioglitazone Released 10 min. 42% 20 min 79% 30 min 95% 45 min102% 

The finished polished tablet also contained the following pioglitazonerelated compounds when tested by HPLC using a YMC-ODS-AQ, 5 μm, 120 Å,4.6×250 mm column, a 0.1 M ammonium acetate buffer:acetonitrile:glacialacetic acid (25:25:1) mobile phase, a 40 μL injection volume, 0.7 mL/minflow rate, 25° C. column temperature and 269 nm wavelength for the UVdectector.

Name Relative Retention Time Amount (%) RS-1 0.7 N.D*. Pioglitazone 1.0RS-2 1.5 0.03 RS-3 3.4 0.04 RS-4 1.2 0.03 RS-5 2.8 0.04 *N.D. = nonedetected

RS-1 is(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-5-hydroxy-2,4-thiazolidinedione.

RS-2 is(z)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4-thiazolidinedione.

RS-3 is(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-thiazolidinedione.

RS-4 is(+/−)-ethyl-2-carbamoyltio-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-]propionate.

RS-5 is ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-propionate.

The final polished tablet was packaged in a 100 cc HDPE bottlecontaining one (1) 2 g SORB-IT® desiccant canister and subjected toaccelerated stability conditions of 40° C. and 75% relative humidity forthree (3) months. After storage, the final polished tablet was testedand exhibited the following pioglitazone HCl dissolution profile whentested in a USP apparatus type 1 at 100 rpm in a pH 2.0 HCl-0.3M KClbuffer solution:

Time % Pioglitazone Released 10 min. 38% 20 min 73% 30 min 92% 45 min101% 

The stored final polished tablet also contained the followingpioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5μm, 120 Å, 4.6×250 mm column, a 0.1 M ammonium acetatebuffer:acetonitrile:glacial acetic acid (25:25:1) mobile phase, a 40 μLinjection volume, 0.7 mL/min flow rate, 25° C. column temperature and269 nm wavelength for the UV dectector.

Name Relative Retention Time Amount (%) RS-1 0.7 N.D.* Pioglitazone 1.0RS-2 1.5 0.03 RS-3 3.4 0.05 RS-4 1.2 0.02 RS-5 2.8 0.04 *N.D. = nonedetected

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1. A pharmaceutical dosage form having a first and second active drug,said dosage form comprising: (a) a controlled release core comprising:i) a core comprising at least one pharmaceutically acceptable excipientand only one active drug that consists of metformin hydrochloride; andii) a sustained release coating surrounding the core; (b) optionally afirst seal coating surrounding the sustained release coating that doesnot contain an active pharmaceutical ingredient and that rapidlydisperses or dissolves in water and (c) an immediate releasepioglitazone layer surrounding the sustained release coating of thecontrolled release core or the first seal coating if present comprisingpioglitazone hydrochloride and a binder wherein the immediate releasepioglitazone layer is free of a surfactant and not less than 90%, of thepioglitazone hydrochloride is released from the dosage form within 30minutes when tested according to the United States Pharmacopeia (USP)26, with Apparatus 1 at 100 rpm, 37° C. and 900 ml of 0.3 M KCl—HClBuffer, pH 2.0, and after storage at 40° C. and 75% relative humidityfor three months, the total pioglitazone related compounds or impuritiesin the dosage form is not more than 0.6% as determined by highperformance liquid chromatography and each individual pioglitazonerelated compound or impurity in the final dosage form is not more than0.25% wherein the pioglitazone related compounds and impurities are: (i)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-5-hydroxy-2,4-thiazolidinedione;(ii)(z)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4-thiazolidinedione;(iii)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-thiazolidinedione;(iv)(+/−)-ethyl-2-carbamoyltio-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-]propionate;and (v) ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-propionate.
 2. Thepharmaceutical dosage form as defined in claim 1 wherein not less than100%, of the pioglitazone hydrochloride is released from the dosage formwithin 45 minutes when tested according to the United StatesPharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37° C. and 900 ml of0.3 M KCl—HCl Buffer, pH 2.0.
 3. The pharmaceutical dosage form asdefined in claim 1 wherein the total pioglitazone related compounds orimpurities are not more than 0.5%.
 4. The pharmaceutical dosage form asdefined in claim 3 wherein each individual pioglitazone related compoundor impurity in the final dosage form is not more than 0.20%.
 5. Thepharmaceutical dosage form as defined in claim 4 wherein each individualpioglitazone related compound or impurity in the final dosage form isnot more than 0.10%.
 6. The dosage form of claim 1 wherein saidcontrolled release core is an osmotic tablet.
 7. The dosage form ofclaim 6 wherein the osmotic tablet consists of: (a) a core comprising:(i) 50-98% of said metformin hydrochloride; (ii) 0.1-40% of a bindingagent; (iii) 0-20% of an absorption enhancer; and (iv) 0-5% of alubricant; (b) optionally an inner seal coat surrounding the core; and(c) a sustained release coating surrounding the core or the inner sealcoat if present comprising: (i) 50-99% of a polymer; (ii) 0-40% of aflux enhancer and (iii) 0-25% of a plasticizer, said membrane having atleast one passageway formed therein for release of the metforminhydrochloride.
 8. The dosage form of claim 1 wherein said core issubstantially free from any gelling or expanding polymer.
 9. The dosageform of claim 1 wherein said controlled release of said metforminhydrochloride provides a Tmax of 8-12 hours.
 10. The dosage form ofclaim 1 wherein said release of the pioglitazone hydrochloride providesa Tmax of 1-12 hours.
 11. The dosage form of claim 10 wherein saidrelease of the pioglitazone hydrochloride provides a Tmax of 1-4 hours.12. A pharmaceutical dosage form comprising: (A) a controlled releaseosmotic tablet comprising: i) a core comprising at least onepharmaceutically acceptable excipient and only one active drug thatconsists of metformin hydrochloride; and ii) a sustained release coatingsurrounding the core wherein the controlled release osmotic tabletexhibits the following dissolution profile when tested in a USP Type 2apparatus at 75 rpms in 900 ml of simulated intestinal fluid with a pHof 7.5 and at 37° C.: 0-25% of the metformin hydrochloride is releasedafter 2 hours; 10-45% of the metformin hydrochloride is released after 4hours; 30-90% of the metformin hydrochloride is released after 8 hours;not less than 50% of the metformin hydrochloride is released after 12hours; not less than 60% of the metformin hydrochloride is releasedafter 16 hours; and not less than 70% of the metformin hydrochloride isreleased after 20 hours; and (B) optionally a first seal coatingsurrounding the sustained release coating that does not contain anactive pharmaceutical ingredient and that rapidly disperses or dissolvesin water; and (C) an immediate release pioglitazone hydrochloride layersurrounding the sustained release coating of the osmotic tablet or thefirst seal coat if present comprising pioglitazone hydrochloride and abinder wherein the immediate release pioglitazone hydrochloride layer isfree of a surfactant and releases not less than 90% of the pioglitazonehydrochloride from the dosage form within 30 minutes when testedaccording to the United States Pharmacopeia (USP) 26, with Apparatus 1at 100 rpm, 37° C. and 900 ml of 0.3 M KCl—HCl Buffer, pH 2.0 and thedosage form contains not more than 0.25% of the following compounds: (i)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-5-hydroxy-2,4-thiazolidinedione;(ii)(z)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4-thiazolidinedione;(iii)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-thiazolidinedione;(iv)(+/−)-ethyl-2-carbamoyltio-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-]propionate;and (v) ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-propionate. 13.The pharmaceutical dosage form as defined in claim 12 wherein not lessthan 95%, of the pioglitazone hydrochloride is released from the dosageform within 30 minutes when tested according to the United StatesPharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37° C. and 900 ml of0.3 M KCl—HCl Buffer, pH 2.0.
 14. The pharmaceutical dosage form asdefined in claim 12 wherein not less than 100%, of the pioglitazonehydrochloride is released from the dosage form within 30 minutes whentested according to the United States Pharmacopeia (USP) 26, withApparatus 1 at 100 rpm, 37° C. and 900 ml of 0.3 M KCl—HCl Buffer, pH2.0.
 15. The dosage form of claim 12 wherein said osmotic tablet core issubstantially free from any gelling or expanding polymer.
 16. The dosageform of claim 12 wherein the osmotic tablet core exhibits the followingdissolution profile when tested in a USP Type 2 apparatus at 75 rpms in900 ml of simulated intestinal fluid with a pH of 7.5 and at 37° C.:0-15% of the metformin hydrochloride is released after 2 hours; 20-40%of the metformin hydrochloride is released after 4 hours; 45-90% of themetformin hydrochloride is released after 8 hours; not less than 60% ofthe metformin hydrochloride is released after 12 hours; not less than70% of the metformin hydrochloride is released after 16 hours; and notless than 80% of the metformin hydrochloride is released after 20 hours.17. The dosage form of claim 12 that contains not more than 0.2% of thefollowing compounds: (i)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-5-hydroxy-2,4-thiazolidinedione;(ii)(z)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4-thiazolidinedione;(iii)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-thiazolidinedione;(iv)(+/−)-ethyl-2-carbamoyltio-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-]propionate;and (v) ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-propionate. 18.The dosage form of claim 12 that contains not more than 0.1% of thefollowing compounds: (i)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-5-hydroxy-2,4-thiazolidinedione;(ii)(z)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene]-2,4-thiazolidinedione;(iii)(+/−)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-3-[2-(5-ethyl-2-pyridyl)ethyl]-2,4-thiazolidinedione;(iv)(+/−)-ethyl-2-carbamoyltio-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-]propionate;and (v) ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl-propionate.